ABSTRACT Lyme disease, which is caused by the spirochete Borrelia burgdorferi, is generally treatable by a 2-4 week course of antibiotics. However, there is strong evidence from studies of human patients and experimental animals that antibiotics do not always clear B. burgdorferi infections. Studies of other bacterial species have revealed genetically-encoded physiological adaptations to antibiotic stresses, such as altering expression levels of target proteins or metabolic enzymes. To gain insight on whether the Lyme spirochete also adapts to antibiotic stresses, we will examine the transcriptomes and proteomes of B. burgdorferi that are exposed to sub-lethal and lethal concentrations of antibiotics that are commonly used to treat human Lyme disease infections. Results of these studies will reveal whether B. burgdorferi possesses genetically-encoded adaptive mechanisms, which can then be targeted for development of improved therapeutics.